PROJECT SUMMARY/ABSTRACT The state of the mother's immune system during pregnancy plays an important role in fetal development and disruptions in this immune balance are associated with a range of neuropsychiatric and neurodevelopmental disorders. Epidemiological and clinical studies have revealed associations between autism spectrum disorders (ASD) and family history of immune system dysfunction. Over the past three decades, analogous increases have been reported in both the incidence of ASD and immune-related disorders, particularly immune hypersensitivities that include allergies and asthma. These trends raise the question of whether immune hypersensitivity and ASD share common causal links. In fact, a case-control report noted that mothers with elevated allergic-associated cytokines during pregnancy were at greater risk of having a child who was later diagnosed with ASD. These data raise the hypothesis that maternal allergic asthma (MAA) produces autism-speci?c neurobehavioral de?cits in offspring and highlight a yet undetermined link between the maternal immune system and risk of ASD. Using a validated mouse model of allergic asthma, we have demonstrated that offspring of MAA dams exhibit ASD-like behavioral de?cits characterized by decreased social interactions and increased repetitive behaviors. This proposal will extend these ?ndings by exploring the in?uence of genetic and environmental factors in protecting against or exacerbating the effects of MAA on offspring brain and behavior development. Speci?cally we will determine [1] how genetic sensitivity to immune hypersensitivity exacerbates the behavioral effects of MAA on offspring, [2] characterize the synergistic effect of MAA and subsequent offspring immune hypersensitivity on ASD-like behavior severity, [3] explore the changes in neuroin?ammation and mast cell activity in the brains of MAA offspring, and [4] correlate peripheral immune cytokines and central nervous system in?ammation with ASD-like behavioral de?cits. The outcomes of these experiments will determine the extent to which maternal asthma contributes to the cause of ASD, identify the contribution of genetic and environmental factors in modulating ASD risk and severity, and inform future development of therapeutic interventions for mitigating the effects of maternal asthma in at-risk populations.